Modification of specific antigen administered prior to transplantation and the route of administration shows promise for donor regulation of the immune response. Specifically, administration of Class I without Class II MHC antigen may prevent sensitization. In addition, pretransplant antigen administration via the portal vein prolongs allograft survival, presumably by processing of the antigen through the liver by an undefined mechanism. This proposal will examine parameters of the immune response to soluble and cellular alloantigens given via the portal vein compared to other routes of administration. Ovalbumin and its immunogenic peptide will be used to examine antigen processing and presentation to T-helper cells and the subsequent development of the delayed type hypersensitivity response, interleukins 1,2,3,4, and tumor necrosis factor (TNF) production. The response to native and heat or ultraviolet B irradiation (UVB) modified cellular alloantigen will be studied. Special attention will be given to the function and products of the Kupffer cells as compared with other macrophage populations. Specific adherence of antigen reactive cells (ARC) to Kupffer cells will be examined as a possible mechanism of sequestration and elimination of ARC. Since Kupffer cells produce prostaglandins and leukotrienes, the immunoregulatory effects of these products will be analyzed. The influence of these parameters on rejection will be examined by transplantation of parathyroid, kidney, heart, and liver allografts in rats. Immunological assessment of recipients of long surviving grafts will be examined for CTLp frequency, anti-idiotypic antibody, suppressor cells, and lymphokine production. In addition, a mouse sponge matrix allograft model will be employed to examine the kinetics of the responsible immune cell subpopulations.